1. Field of the Invention
The present invention relates to a process for preparing an oral formulation of felodipine, and more particularly to a process that manufactures the felodipine formation with sustained releasing efficiency.
2. Description of Related Art
Felodipine is a calcium blocker that efficiently promotes oxygen and blood supplement to the coronary artery and dilates the periphery of blood vessels. Therefore, felodipine is widely used in clinic for treating patients of coronary stenosis and hypertension. However, conventional felodipine formulations cannot be released over a period of more than a couple of hours so that patients have to take felodipine-containing medicaments frequently. If the patients forget to take felodipine or cannot do so during sleep, no sustained protective effects of felodipine are provided. Consequently, the patients confront a high risk of suffering from a heart attack.
There is an existed pharmaceutical preparation of sustained-release medicine, as described in U.S. Pat. No. 4,803,081. U.S. Pat. No. 4,803,081 disclosed an extended release preparation of an active compound, including felodipine, with very low solubility. The conventional preparation contains the active compound dissolved or dispersed in a semi-solid or liquid non-ionic solubilizer as well as a process for the preparation thereof. The process of U.S. Pat. No. 4,803,081 demands the use of the amount by weight of the solubilizer at least equal to the amount by weight of the active compound. It is noted that the solubilizer used according to U.S. Pat. No. 4,803,081 is a non-ionic surfactant, which causes an insufficient dissolubility to the inert-dissolving felodipine. Therefore, felodipine would not be well mixed with other ingredients contained inside the medicine, unless felodipine has to be dissolved in non-ionic surfactant (preferably polyoxyl 40 stearate) first and then mixed with a carrier material, such as HPMC, xanthan gum, guar gum and calcium phosphate. Inevitably, two steps for admixing are required according to U.S. Pat. No. 4,803,081.
There is still a need in this art of a more economical process for the manufacture of sustained release medicines including felodipine.
An objective of the present invention is to provide a process for preparing orally administered, sustained-release felodipine formulations by means of one-step mixing. The process according to the present invention comprising mixing felodipine together with at least an ionic surfactant or hydrophilic polymer and at least a release-controlling excipient to form a uniform felodipine mixture. The release-controlling excipient is selected from hydrophilic colloid, hydrophobic cellulose and wax.
Preferably, the ionic surfactant employeds according to the present invention includes sodium dioctylsulfonyl succinate or sodium lauryl sulfate.
Preferably, the hydrophilic polymer employed according to the present invention includes polyvinyl pyrrolidone (PVP), hydroxyethyl cellulose (HEC), hydroxy propyl cellulose (HPC), hydroxypropylmethyl cellulose (HPMC) or polyvinyl alcohol (PVA).
Preferably, the release-controlling excipient employed according to the present invention includes gelatin, shellac, hydroxypropylmethyl cellulose (HPMC), methylcellulose (MC), ethylcellulose (EC), hydroxypropylmethyl cellulose phthalate (HPMCP), cellulose phthalate acetate (APC), methacrylic acid/methyl methacrylate copolymers, polyvinyl acetate phthalate (PVAP), glyceryl behenate, paraffin or carnauba wax.
The process according to the present invention may further comprise mixing a diluent with the felodipine mixture. The diluent employed according to the present invention includes microcrystalline cellulose, starch, lactose, silicon dioxide, calcium biphosphate, calcium phosphate, calcium carbonate, magnesium carbonate, aluminum silicate, magnesium silicate or mannitol. Preferably, the diluent is microcrystalline cellulose, lactose, silicon dioxide or calcium biphosphate.
The process according to the present invention may further comprise mixing a lubricant with the felodipine mixture. Preferably, the lubricant employed according to the present invention is talc powder, stearic acid, stearyl acetate, sodium stearyl fumarate or glyceryl behenate.
The process according to the present invention may further comprise compressing the felodipine mixture into tablets.
The process according to the present invention may further comprise encapsulating the felodipine mixture.
The process according to the present invention may further comprise mixing the felodipine mixture with water or an organic solvent, and granulating the resultant mixture into granules by a conventional wet-granulation method. The organic solvent employed includes alcohol, acetone, isopropanol, dichloromethane or other dissolvable media. The process according to the present invention may further comprise drying the granules followed by compressing the dried granules into tablets or encapsulating the dried granules. In this respect, preferably, the process according to the present invention further comprises coating the tablets with a light-resisting film. More preferably, the light-resisting film is made of material selected form the group consisting of hydroxypropylmethyl cellulose, polyethylene glycol, titanium dioxide and ferrous oxide. In a preferred embodiment of the process according to the present invention, the granules are dried until a water-containing ratio of 0.4% to 6% (w/w) of the granules is attained.
Further benefits and advantages of the present invention will become apparent after reading the detailed description.